Adult growth hormone deficiency metabolic alterations and evaluation of different risk groups

Hugo L. Fideleff¹, Alberto Chervin², Ana Giaccio¹, Patricia Sobrado¹, Ricardo Barmat¹, Hugo Boquete¹, on behalf of Kabi International Metabolic Study (KIMS) Argentine Group³

¹ Unidad de Endocrinología, Departamento de Medicina, Hospital T. Alvarez;
² Servicio de Endocrinología, Hospital Santa Lucía;
³ KIMS Argentine Group: Darío Bruera (Hosp. de Clínicas, Córdoba), Alberto Chervin (Hosp. S. Lucía), Haraldo Claus Hernberg  (Hosp. Alemán), Hugo L. Fideleff (Hosp. Alvarez), Oscar Levalle (Hosp. Durand), Mirta Miras (Hosp. de Niños, Córdoba), Isaac Sinay (Hosp. Francés), Gracia Stalldecker (Hosp. Pirovano)

Dirección Postal: Dr. Hugo L. Fideleff, Unidad de Endocrinología, Hospital T. Alvarez, Aranguren 2701, Buenos Aires 1406, Argentina. Fax: (54-11) 4612-6563. e-mail: hugofideleff@arnet.com.ar

Abstract
Adult growth hormone deficiency (AGHD) is an heterogeneous clinical entity characterized by increased cardiovascular morbidity and mortality, alterations in body composition, osteoporosis and impaired quality of life. In order to characterize higher risk subpopulations we studied 77 patients with AGHD, 35 with childhood onset (AGHD-CO): CA 18-44 yr.; 13 females and 22 males, and 42 with adult onset (AGHD-AO): CA 25-70 yr.; 22 females and 20 males. IGF-I, lipid profile, glycemia and glycosylated hemoglobin were measured. Cardiological evaluation: blood pressure, electrocardiogram, ergometry and 2D echocardiogram with mitral Doppler, evaluation of diastolic function (A/E waves ratio and deceleration time), systolic function (ejection and shortening fractions) and Cardiac Mass Index (CMI). The Body Mass Index and waist circumference were recorded. Total body composition and bone mineral density were evaluated by densitometry, and the following bone markers were measured: osteocalcin, bone-specific alkaline phosphatase, carboxyterminal propeptide of type I procollagen, Pyridinoline and Deoxipyridinoline. The subset of females with AGHD-AO had higher levels of total cholesterol: 240 mg/dl (156-351) (p< 0.005), LDL: 140 mg/dl (62-262) (p< 0.04) and of total cholesterol / HDL: 4.04 (3.12-12.7) (p< 0.04); while females with AGHD-CO had a decreased CMI: 62 g/m² (53-107) (p< 0.01), lower A/E waves ratio: 0.56 (0.39-0.72) (p< 0.01) and lower deceleration time: 164 msec. (135-210) (p< 0.01). The subset of males with AGHD-AO had a greater waist circumference: 98 cm (83-128) (p< 0.03) and males with AGHD-CO had a lower shortening fraction: 41% (30-49) (p< 0.006) and lower deceleration time: 153.5 msec. (127-230) (p< 0.03). In both genders, the bone mineral content was lower in patients with AGHD-CO (females p< 0.02, males: p< 0.0008). Our findings confirm the differences in impairment in AGHD patients, which are mainly dependent on gender and the time of onset of the deficiency, and thus demonstrate the heterogeneity of the syndrome.

Key words:  Growth hormone; Adult growth hormone deficiency; Metabolic alterations

Resumen
Deficiencia de hormona de crecimiento en el adulto. Alteraciones metabólicas y evaluación de diferentes grupos de riesgo. El déficit de hormona de crecimiento (GH) del Adulto (AGHD) es una entidad clínica heterogénea caracterizada por incremento de la morbimortalidad cardiovascular, cambios en la composición corporal, osteoporosis y deterioro de la calidad de vida. Para caracterizar subpoblaciones con mayor riesgo de afectación, estudiamos 77 pacientes AGHD, 35 de inicio en la infancia (AGHD-CO): EC 18-44 a; 13 mujeres y 22 varones, y 42 de inicio en la adultez (AGHD-AO): EC 25-70 a; 22 mujeres y 20 varones. Se midió IGF-I, perfil lipídico, glucemia y hemoglobina glicosilada. Evaluación cardiológica: tensión arterial, electrocardiograma, ergometría y ecocardiograma bidimensional con Doppler mitral, evaluando función diastólica (relación ondas A/E y tiempo de desaceleración), función sistólica (fracciones de eyección y acortamiento) e índice de masa cardíaca (IMC). Se registró el índice de masa corporal y la circunferencia de cintura. Se evaluó, mediante densitometría, la composición corporal total y la densidad mineral ósea y se dosaron marcadores óseos: osteocalcina, fosfatasa alcalina fracción ósea, propéptido tipo I carboxiterminal del procolágeno, Pyridinolina y Deoxipyridinolina. El subgrupo de mujeres AGHD-AO presentó mayores niveles de colesterol total: 240 mg/dl (156-351) (p< 0.005), LDL: 140 mg/dl (62-262) (p< 0.04) y de colesterol total / HDL: 4.04 (3.12-12.7) (p< 0.04); mientras que las mujeres AGHD-CO presentaron menor IMC: 62 g/m² (53-107) (p< 0.01), menor relación A/E: 0.56 (0.39-0.72) (p< 0.01) y menor tiempo de desaceleración: 164 mseg (135-210) (p< 0.01). El subgrupo de varones AGHD-AO presentó mayor circunferencia de cintura: 98 cm (83-128) (p< 0.03) y los varones AGHD-CO, menor fracción de acortamiento: 41% (30-49) (p< 0.006) y menor tiempo de desaceleración: 153.5 mseg (127-230) (p< 0.03). En ambos sexos, el contenido mineral óseo fue menor en los pacientes AGHD-CO (mujeres p< 0.02, varones: p< 0.0008). Nuestros hallazgos confirman la diferente afectación de los pacientes AGHD, en particular en relación al sexo y al momento de inicio de la deficiencia, demostrando la heterogeneidad del síndrome.

Palabras clave:  Hormona de crecimiento; Déficit de hormona de crecimiento del adulto; Alteraciones metabólicas

Adult growth hormone (GH) Deficiency (AGHD) started to be recognized as a clinical entity in the late 80’s^1,2. When a syndrome was defined in hypopituitary patients characterized by increased cardiovascular morbidity and mortality, premature atherosclerosis with changes in lipid profile and in insulin sensitivity, alterations in body composition including increased fat mass, reduced lean body mass and redistribution of body water, reduced physical performance, osteoporosis and impaired quality of life^3-7. Two groups of patients were identified: those with childhood onset GH deficiency (AGHD-CO) and those with adult onset GH deficiency (AGHD-AO). Later, the heterogeneity of the clinical presentation was confirmed in both groups of patients. Such heterogeneity is attributed not only to the onset but also to the etiology (functional or organic), the duration and severity of the deficiency, gender and impairment of other pituitary hormones^{8, 9}.
      Based on our recent experience in a multicenter study on the follow-up of AGHD patients, we attempted to make a critical analysis of the degree of clinical, metabolic, cardiovascular and bone impairment in the different subsets of patients evaluated, in order to characterize different higher risk subpopulations.

Material and Methods

A total of 77 patients were studied: 35 AGHD-CO, with an age range between 18 and 44 years (13 females and 22 males), and 42 AGHD-AO, between 25 and 70 years (22 females and 20 males). The etiologies of the deficiency for AGHD-CO were: idiopathic (n = 22); craniopharyngioma (n = 6); perinatal trauma or asphyxia (n= 2); meningitis, oligodendroglioma, cholestea-toma, empty sella and pinealoma (n =1 each). The etiologies for AGHD-AO were: non-functioning pituitary tumor ( n = 15); prolactinoma (n = 7); Sheehan’s syndrome (n = 4); craniopha-ryngioma (n=4); Cushing’s disease (n = 3); pituitary epidermoid cyst (n=2); pituitary granuloma, hypophysitis, empty sella, myoblastoma, dysgerminoma, acromegalia and idiophatic (n = 1 each).
      In the AGHD-CO group, 19 patients had received GH therapy during childhood, but had discontinued such therapy at least 1 year before their enrollment in the study.
      The diagnosis of AGHD was made by the Insulin Tolerance Test (ITT)¹⁰, and in patients in whom this test is contraindicated, an arginine test was performed¹¹. In patients with isolated or idiopathic deficiency, both tests were performed. Only patients with severe GH deficiency, defined by a peak GH response < 3 µg/L to any of the stimulation tests, were enrolled¹⁰. The following parameters were evaluated in all patients: total cholesterol, HDL, LDL, triglycerides, total cholesterol/ HDL ratio, glycemia and glycosylated hemoglobin A1 or A1C. Two different assays were used to determine plasma levels of GH. First, an IRMA-Magnetic Solid Phase was used (Serono Maia Clone, Milan, Italy), calibrated against the 1^st IRP 66/217. Then, a two-site chemiluminiscent enzyme immunometric assay (ICMA, Immulite, Diagnostic Products Corporation, Los Angeles, USA) was used, calibrated against the WHO IRP 80/505. The equation for the linear regression line comparing the two methods was log Y = 1.03 . log X – 0.09, where X was the IRMA and Y was the ICMA (r= 0.97; standard error of estimate = 0.11). Serum IGF-I level was measured using IRMA after acid-ethanol extraction (Diagnostic Systems Laboratories, Inc., Webster, Texas, USA). Age -and sex- adjusted IGF-I values were obtained from a reference population of blood donors: 384 serum samples from healthy adults (191 males and 193 females) with an age range between 18-70 years. The individual IGF-I SD scores could then be calculated. Cardiological evaluation included systolic and diastolic blood pressure, electrocardiogram, ergometry and 2D echocardiogram with mitral Doppler (Esaote Model AU3). Diastolic function (A/E waves ratio and deceleration time), systolic function (ejection fraction and shortening fraction) and cardiac mass index (CMI) were evaluated. The body mass index (BMI) and waist circumference were recorded. Total body composition: lean body mass (LBM), fat mass and bone mineral content (BMC) were evaluated, and bone mineral density (BMD) was measured at the lumbar spine, femoral neck and for total body with a Lunar DPX-L densitometer. As the population studied included patients under 20 and older than 65, in all cases the BMD was ex-pressed as Z-score to make the sample homogeneous. In 10 AGHD-CO and 21 AGHD-AO patients, bone formation markers were measured: Osteocalcin (RIA, Diagnostic Systems Laboratories, Inc., Webster, Texas, USA), bone - specific alkali-ne phosphatase (BS AP) and carboxyterminal propeptide of type I procollagen (PICP) (Elisa, Metra Biosystems, Inc., Mountain View, CA, USA). Bone resorption markers: Pyridinoline (Pyr) and Deoxipyridinoline (DPyr) (Elisa, Metra Biosystems, Inc., Mountain View, CA, USA ) were measured in 8 AGHD-CO and 19 AGHD-AO patients.
      The statistical analysis was performed by the Mann-Whitney test¹² to compare the various variables between AGHD-CO vs. AGHD-AO separated by gender, except for bone markers, where data were analyzed by comparing AGHD-CO vs. AGHD-AO with no separation by gender. BMC was correlated vs. LBM by the Spearman rank order correlation test¹³.
      Written informed consent was obtained from all patients, and the Education and Research Committee approved the study.

Results

Clinical Characteristics

Results of BMI, waist circumference, systolic and diastolic blood pressure are shown in Table 1. Out of 13 females, 7 (54%) in the AGHD-CO group had a BMI > 25 kg/m² , 5 of them (39%) had a BMI consistent with increased cardiovascular risk (BMI > 27 kg/m²) and 3 of these 5 females (23%) had obesity (BMI > 30 kg/m²). Out of 22 females, 15 (68%) in the AGHD-AO group had a BMI > 25 kg/m², 10 of them (46%) had a BMI > 27 kg/m² and 6 of these 27 females (27%), had a BMI > 30 kg/m². Out of 22 males, 13 (59%) in the AGHD-CO group had a BMI > 25 kg/m², 9 of them (4%) had a BMI > 27 kg/m² and 4 of these 9 males (18%), had a BMI > 30 kg/m². Out of 20 males, 15 (75 %) in the AGHD-AO group had a BMI > 25 kg/m², 12 of them (60%) had a BMI > 27 kg/m² and 7 of these 12 males (35%), had a BMI > 30 kg/m².

TABLE 1.- Adult Growth Hormone Deficiency (AGHD): anthropometric, biochemical and cardiological parameters (values expressed as median and range)

Waist circumference consistent with central obesity (> 84 cm in females and > 92 cm in males) was found in 7/13 (54%) AGHD-CO females, 10 /22 (46%) AGHD-AO females, 8/22 (36%) AGHD-CO males and 16/20 (80%) AGHD-AO males.
      Increased systolic blood pressure (³140 mmHg) was observed in 3/13 (23%) AGHD-CO females and in 4/22 (18%) AGHD-AO females. Increased systolic and diastolic blood pressure (³95 mmHg) was observed in 1/22 AGHD-CO males, while in AGHD-AO males, systolic blood pressure was elevated in 5/20 (25%) and diastolic blood pressure was elevated in 3/20 (15%).

IGF-I measurement (Table 1)

IGF-I SDS was below the reference values for the normal population (below - 2 SDS) in 12/13 AGHD-CO females (92%), in 20/22 AGHD-AO females (91%), in 19/22 AGHD-CO males (86%) and in 14/20 AGHD-AO males (70%).

Lipid Profile and Carbohydrate Metabolism

Results of total cholesterol, LDL, HDL, total cholesterol/ HDL ratio, triglycerides, glycemia and glycosilated hemo-globin are shown in Table 1.

Total cholesterol levels above 200 mg/dl were observed in 2/13 AGHD-CO females (18%), in 14/22 AGHD-AO females (65%), in 16/22 AGHD-CO males (71%) and in 13/20 AGHD-AO males (64%), and levels above 240 mg/dl were observed in 10/22 AGHD-AO females (47%), in 5/22 AGHD-CO males (24%) and in 9/20 AGHD-AO males (45%).
      LDL values were increased (> 160 mg/dl) in 9/22 AGHD-AO females (39%), in 9/22 AGHD-CO males (42%) and in 10/20 AGHD-AO males (50%) and HDL levels were decreased (< 45 mg/dl in females and < 35 mg/dl in males) in 3/13 AGHD-CO females (20%), in 5/22 AGHD-AO females (24%), in 8/22 AGHD-CO males (36 %) and in 6/20 AGHD-AO males (30%).
      Total cholesterol/HDL ratio > 4.5 (consistent with increased cardiovascular risk) was observed in 3/13 AGHD-CO females (20%), in 8/22 AGHD-AO females (35%), in 14/22 AGHD-CO males (65%) and in 14/20 AGHD-AO males (70%).
      Triglycerides levels above 200 mg/dl were observed in none of the AGHD-CO females, in 3/22 AGHD-AO females (14%), in 9/22 AGHD-CO males (42%) and in 4/20 AGHD-AO males (18%).
      No AGHD-CO female patient had total cholesterol levels above 240 mg/dl, LDL levels above 160 mg/dl or triglycerides above 200 mg/dl.
      In all cases glycemia and glycosilated hemoglobin levels were within normal reference values for each method used.

Cardiological evaluation

Results of CMI, ejection fraction, fractional shortening, A/E waves ratio and deceleration time are shown in Table 1.
      A trend towards a restrictive echocardiographic pattern of diastolic function (A/E waves ratio < 0.84) was observed in 12/13 AGHD-CO females (92%), in 11/22 AGHD-AO females (50%), in 18/22 AGHD-CO males (82%) and in 8/20 AGHD-AO males (40%). A prolonged diastolic function pattern (A/E waves ratio > 1.00) was observed in none of the AGHD-CO females, 7/22 AGHD-AO females (32%), in 2/22 AGHD-CO males (9%) and in 4/20 AGHD-AO males (20%).
      A mild decreased in ejection fraction (< 50%) was observed in 1 AGHD-CO male and in 2 AGHD-AO males.
      Decreased CMI (< 90 g/m²) was observed in 11/13 AGHD-CO females (85%), in 11/22 AGHD-AO females (50%), in 12/22 AGHD-CO males (55%) and in 11/20 AGHD-AO males (55%). CMI consistent with cardiac hypertrophy was observed only in 1 AGHD-AO male patient (> 130 g/m²).

Body composition, BMD and Bone Markers

Results of body composition and BMD are shown in Table 2.

TABLE 2.- Adult Growth Hormone Deficiency (AGHD): Body composition and densitometry (values expressed as median and range)

A positive correlation was found between bone mineral content (BMC) and lean body mass (r= 0.84, p=0.001). Serum and Urinary bone turnover markers could be measured in 10 AGHD-CO patients and in 21 AGHD-AO patients; therefore results (median and range) are described for both genders as a whole. Serum osteocalcin levels (µg/L) were: 3.65 (1.10-12.00) for AGHD-CO and 3.50 (1.00-7.40) for AGHD-AO; BS AP levels (U/L) were 19 (6-32) for AGHD-CO and 14 (7-47) for AGHD-AO, while PICP levels (µg/L) were 96 (50-216) for AGHD-CO and 82 (47-198) for AGHD-AO. Urinary Pyr levels (nM/nM of creatinine) were 23.5 (5.0-53.0) for AGHD-CO and 30 (6.5-132) for AGHD-AO and Dpyr levels (nM/nM of creatinine) were 6 (2.4-13.3) for AGHD-CO and 6 (3.7-35.5) for AGHD-AO.  Osteocalcin levels were below reference values in AGHD-CO: 3/10 (30%) and in AGHD-AO: 13/21 (62%). PICP levels were decreased in 3/10 (30%) AGHD-CO patients and in 6/21 (29%) AGHD-AO patients, and increased in 1/10 AGHD-CO patients and in 1/21 AGHD-AO patients. BS AP was decreased in 1/10 AGHD-CO patients and in 7/21 (33%) AGHD-AO patients, and increased in 1 AGHD-AO patient. Pyr levels were decreased in 3/10 (30%) AGHD-CO patients and in 4/21 (19%) AGHD-AO patients, and increased in 4/10 (40%) AGHD-CO patients and in 8/21 (38%) AGHD-AO patients. Dpyr was elevated in 5/10 (50%) AGHD-CO patients and in 7/21 (33%) AGHD-AO patients. No significant differences were found in any of these parameters between AGHD-CO and AGHD-AO.

Discussion

Since the publication of the first papers reporting increased cardiovascular morbidity and mortality in hypopituitary patients receiving replacement therapy for all hormone deficiencies except for somatrotropin deficiency, many authors have reported alterations in the lipid, carbohydrate and phosphocalcium metabolism and in the quality of life^1-7. Different subsets of patients who are at different risk levels of impairment in each of the aforementioned areas have been identified. The two clearly defined groups include patients with  childhood onset GH deficiency and patients with adult onset GH deficiency^{8, 9, 14}. Possible gender-dependent differences in impairment have also been reported^{14, 15}. Despite the long time elapsed and the large number of publications, many doubts still persist. For this reason, a critical re-evaluation of the degree of impairment of the various parameters has been proposed.
      As alterations secondary to GHD have been well characterized in severe deficiencies but not in partial GH deficiencies, we have only included those patients with a GH response below 3 µg/L, as recommended by various international consensus^{10, 16}. Severe GH deficiency in our patients would be confirmed by the high percentage of patients with IGF-I levels below -2 SDS, which correlates with low GH secretion. Our AGHD-CO patients had IGF-I levels significantly lower than AGHD-AO patients, as reported by many authors^{8, 17, 18}. This could be attributed to the fact that many AGHD-CO patients might have a more severe and/or more prolonged somatotropin deficiency.
      It is interesting to highlight the significant tendency towards overweight and obesity in our patients, since only 25% to 46% of patients, depending on the subset evaluated, had a BMI consistent with normal weight, a finding supported by many authors^{19, 20}. In agreement with this finding, our patients showed a high percentage of fat mass with a concomitant decrease in lean body mass, which was equally observed in AGHD-CO and AGHD-AO patients of both genders. However, Korangy et al.²¹ reported an increase in body fat percentage greater than predicted in AGHD-CO patients, in spite of not having found any differences in absolute values of body fat between AGHD-CO and AGHD-AO patients. This is aggravated by the important prevalence of central obesity, found in up to 80% of our AGHD-AO male patients and evaluated by increased waist circumference. It is well known that this fact is associated to increased cardio-vascular morbidity and mortality, as shown in epide-miological studies^22-24. Therefore, some authors^{3, 25} have established an analogy between AGHD and the endocrine-metabolic syndrome reported by Reaven²⁶ in 1988. As regards carbohydrate metabolism, none of our patients showed alterations in fasting glycemia or glycosilated hemoglobin.
      GH influences both production and secretion of lipoproteins by the liver and their plasma clearance²⁵. This would partly account for the high percentage of patients (over 50%) with total cholesterol levels above 200 mg/dl and total cholesterol / HDL ratio above 4.5. This would be worsened by the fact that approximately one-third of our patients had elevated LDL levels. The lower percentage of alterations in lipid and lipoprotein levels found in AGHD-CO females is worth noting. This could possibly be attributed to the higher prevalence of isolated and idiopathic GHD in this subgroup, with other axes, specially the gonadotropic axis, being unimpaired. The significance difference in chronological ages between groups should also be noted.
      In our experience, a variable percentage of patients of both genders showed a mild increase in systolic blood pressure. However, elevated diastolic blood pressure was detected only in some males. Multicenter studies have reported hypertension in 26% of AGHD patients²⁰, which is similar to the prevalence of hypertension in the general population²⁷. Hypertension in some of these patients could be attributed to the impaired vascular reactivity related to a defect in the generation and/or metabolism of nitride oxide in the vascular wall^{28, 29}.
      The high prevalence of impaired diastolic function was noticeable, with a predominance of restrictive patterns in AGHD-CO patients and a larger number of cases with prolonged pattern in AGHD-AO patients. The predo-minance of restrictive pattern in AGHD-CO patients (physiological during childhood) could be assumed to be related to certain difficulty in diastolic function maturation due to somatotropin deficiency³⁰. As the prolonged diastolic pattern is frequently observed during aging, a relatively early diastolic function impairment could possibly be assumed in our AGHD-AO patients. Some papers report variable percentages of patients with impaired systolic function^{31, 32}, while others do not find such impairment³³. In our experience, we found only a small number of male patients with a minimal decrease in the ejection fraction both in the AGHD-CO and AGHD-AO group. It is interesting to point out that in our series the percentage of patients with reduced cardiac mass exceeded 50%, reaching 85% in females of the AGHD-CO group. The GH / IGF-I system targets and activates specific high affinity sarcolematic receptors and induces multiple signal transduction pathway which results in an increased protein synthesis and promotes myocyte cell mass growth³⁴. This would partly account for the reduced cardiac mass found in our AGHD patients.
      Our patients showed a clear tendency towards abnormally low values of bone mineral density both at the lumbar spine and femoral neck. Bone mineral content values were lower in the AGHD-CO group than in the AGHD-AO group, for both genders; this could be partly due to the smaller size of bones in these patients due to their shorter stature. It is accepted that GH plays an important role in the acquisition of an adequate peak bone mass, even after completing lineal growth, and in maintaining such bone mass during adulthood³⁵. Hypopituitary AGHD-AO patients receiving standard endocrine replacement therapy have been reported to have osteopenia, as compared to age-matched healthy controls^{36, 37}. An increased incidence of osteoporotic fractures has also been observed in this group of patients³⁸; furthermore, some data indicate that the severity of bone loss would be proportional to the degree of GH deficiency³⁵. On the other hand, bone remodeling activity can be evaluated by measuring bone formation and resorption markers. Many studies resulted in controversial data when measuring these markers^{8, 39, 40}. In our experience, 30% of patients showed a clear decrease in bone formation markers, and an increase in bone resorption markers, which accounts for the decrease observed in bone mineral content. However, this finding has not been consistent, since some cases had increased markers of bone apposition and decreased markers of bone resorption. The correlation observed between bone mineral content and lean body mass (primarily an expression of muscular tissue) could be supported by the "mechanostat theory", which proposes that because of a biomechanical effect, the greater the muscular mass, the higher the bone mineral content⁴¹.
      The importance of maintaining normal GH concen-trations throughout life has been well established. Many papers have been published and much information is available on severe GH deficiency in adults. Data on morbidity and mortality, impaired bone metabolism, prevalence of metabolic and cardiovascular risk factors and quality of life have accumulated in recent years. Our findings confirm the differences in impairment in AGHD patients, which are mainly dependent on gender and the time of onset of the deficiency, and thus demonstrate the heterogeneity of the syndrome.
      At present, GH replacement therapy can be consi-dered to be safe, given the scarce adverse effects. It is also considered as a supplement to other replacement therapies for other impaired axes in pituitary patients⁴⁰. However, the evaluation of the effects of medium and long-term treatment on the various areas involved will make it possible to clarify the benefits and risks of extending therapy to all patients with AGHD.

Acknowledgements: We wish to thank Carina Fideleff for her assistance in the correction of the English version. This study was partially supported by Pharmacia Argentina - Pfizer SRL.

References

1. Jorgensen JOL, Thuesen L, Ingemannhansen T et al. Beneficial effects of growth hormone treatment in GH deficient adults. Lancet 1989; 1: 1221-5.         [ Links ]
2. Salomon F, Cuneo RC, Hesp R, Sonksen PH. The effects of treatment with recombinant human growth hormone on body composition and metabolism in adults with growth hormone deficiency. N Engl J Med 1989; 321: 1797-803.         [ Links ]
3. De Boer H, Blok G-J, Van der Veen EA. Clinical aspects of growth hormone deficiency in adults. Endocr Rev1995; 16: 63-86.         [ Links ]
4. Rosén T, Edén S, Larsson G, Wilhelmsen L, Bengtsson B-Å. Cardiovascular risk factors in adult patients with growth hormone deficiency. Acta Endocrinol (Copenh) 1993; 129: 195-200.         [ Links ]
5. Markussis V, Beshyah SA, Fisher C, Sharp P, Nicolaides AN, Johnston DG. Detection of premature atherosclerosis by high-resolution ultrasonography in symptom-free hypopituitary adults. Lancet 1992; 340: 1188-92.         [ Links ]
6. Rosén T, Bengtsson B-Å.  Premature mortality due to car-diovascular diseases in hypopituitary. Lancet 1990; 336: 285-8.         [ Links ]
7. Cuneo RC, Salomon F, McGauley GA , Sönksen PH. The growth hormone deficiency syndrome in adults. Clin Endocrinol 1992; 37: 387-97.         [ Links ]
8. Attanasio AF, Lamberts SWJ, Matranga AMC, et al. Adult growth hormone (GH)-deficient patients demonstrate heterogeneity between childhood onset and adult onset before and during human GH treatment. J Clin Endocrinol Metab 1997;  82: 82-8.         [ Links ]
9. Shalet SM, Toogood A, Rahim A, Brennan B. The diagnosis of growth hormone deficiency in children and adults. Endocr Rev 1998; 19(2): 203-23.         [ Links ]
10. Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of adults with growth hormone deficiency: summary statement of the Growth Hormone Research Society workshop on adult growth hormone deficiency. J Clin Endocrinol Metab 1998; 83: 379-81.         [ Links ]
11. Fideleff HL, Frigeri AE, Sobrado PG, Llano MN, Ruibal GF, Boquete HR. Reproducibility and Variability of the Arginine test in Normal Adults: Comparison between sexes. Medicina (Buenos Aires)1999; 59: 249-53.         [ Links ]
12. Siegel S. Non parametric statistics for the behavioral sciences, 5th ed. New York: Mc Graw, 1990, p 143-55.         [ Links ]
13. Siegel S. Non parametric statistics for the behavioral sciences, 5th ed. New York: Mc Graw, 1990, p 233-45.         [ Links ]
14. Johannsson G, Bjarnason R, Bramnert M et al. The individual responsiveness to growth hormone (GH) treatment in GH- deficient adults is dependent on the level of GH- binding protein, body mass index, age and gender. J Clin Endocrinol Metab 1996; 81: 1575-81.         [ Links ]
15. Fisker S, Jorgensen JO, Vahl N, Orskov H, Christiansen JS. Impact of gender and androgen status on IGF-I levels in normal and GH-deficient adults. Eur J Endocrinol 1999; 141: 601-8.         [ Links ]
16. Thorner MO, Bengtsson B-Å, Ho KY et al. The diagnosis of growth hormone deficiency in adults. J Clin Endocrinol Metab 1995; 80: 3097-8.         [ Links ]
17. Janssen YJ, Frolich M, Roelfsema F. A low starting dose of genotropin in growth hormone-deficient adults. J Clin Endocrinol Metabol 1997; 82 (1): 129-35.         [ Links ]
18. Beshyah SA, Shahi M, Skinner E, Sharp P, Foale R, Johnston D. Cardiovascular effects of growth hormone replacement therapy in hypopituitary adults. Eur J Endocrinol 1994; 130: 451-8.         [ Links ]
19. Attanasio AF, Howell S, Bates PC et al. Body compo-sition, IGF-I and IGFBP-3 concentrations as outcome measures in severely GH- deficient (GHD) patients after childhood GH treatment: a comparison with adult on- set GHD patients. J Clin Endocrinol Metab 2002; 87 (7): 3368-72.         [ Links ]
20. Luger A. Baseline characteristics of patients enrolled in KIMS. In: Bengt-Åke Bengtsson B-Å, Monson JP (eds). GH Replacement in Adults. The first 5 years of KIMS. Oxford PharmaGenesis^TM Ltd., Oxford, UK, 2000, p 105-11.         [ Links ]
21. Koranyi J, Svensson J, Götherström G, Sunnerhagen KS, Bengtsson B-Å, Johannsson G. Baseline Characteristics and the Effects of five years of GH replacement therapy in adults with GH deficiency of childhood or adulthood onset: a comparative, prospective study. J Clin Endocrinol Metab 2001, 86: 4693-9.         [ Links ]
22. Bates AS, Vant Hoff W, Jones PJ, Clayton RN. The Effect of Hypopituitarism on Life Expectancy. J Clin Endocrinol Metab 1996;  81: 1169-72.         [ Links ]
23. Larsson B, Svardsudd K, Welin L, Wilhelmsen L, Björntorp P, Tibblin G. Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: a 13 year follow-up of participants in the study of men born in 1913. Br Med J 1984; 288: 1401-4.         [ Links ]
24. Wing RR, Jefferey RW, Burton LR, Kuller LH, Thorson C, Folsom AR. Change in waist-hip ratio with weight loss and its association with change in cardiovascular risk factors. Am J Clin Nutr 1992; 55: 1086-92.         [ Links ]
25. Rosén T, Johannsson G, Johansson J-O, Bengtsson B-Å. Consequences of growth deficiency in adults and the benefits and risks of recombinant human growth hormone treatment. Horm Res 1995; 43: 93-9.         [ Links ]
26. Reaven GH. Role of insulin in human disease. Diabetes 1988; 37: 1595-607.         [ Links ]
27. Dannenberg AL, Garrison RJ, Kannel WB. Incidence of hypertension in the Framingham Study. Am J Publ Health 1988; 78: 676-9.         [ Links ]
28. Christ ER et al. Growth hormone replacement in adults with growth hormone deficiency improves vascular endothelial function. Clin Endocrinol 1999; 51: 21-5.         [ Links ]
29. McCallum RW, Petrie JR, Dominiczak AF, Connell JM. Growth Hormone Deficiency and Vascular Risk. Clin Endocrinol 2002; 57: 11-24.         [ Links ]
30. Bengtsson B-Å, Christiansen JS, Cuneo RC, Saccà L.  Cardiovascular Effects of GH. J Endocrinol 1997; 152: 1-3.         [ Links ]
31. Colao A, Marzullo P, Di Somma C, Lombardi G. Growth Hormone and the Heart. J Clin Endocrinol Metab 2001; 54: 137-54.         [ Links ]
32. Longobardi S, Cuocolo A, Merola B et al. Left ventricular function in young adults with childhood ad adulthood onset growth hormone deficiency. Clin Endocrinol 1998; 48: 137-43.         [ Links ]
33. Valcavi R, Gaddi O, Zini M, Iavicoli M, Mellino U, Portioli I. Cardiac Performance and Mass in Adults with Hypopi-tuitarism: Effects of One Year of Growth Hormone Treatment. J Clin Endocrinol Metab1995; 80: 659-66.         [ Links ]
34. Fazio S, Palmieri EA, Biondi B, Cittadini A, Saccà L. The role of the GH-IGF-I axis in the regulation of myocardial growth: from experimental models to human evidence. Eur J Endocrinol 2000; 142: 211-6.         [ Links ]
35. Colao A, Di Somma C, Pivonello R, et al. Bone Loss is correlated to the severity of growth hormone deficiency in adult patients with hypopituitarism. J Clin Endocrinol Metab 1999; 84: 1919-24.         [ Links ]
36. Holmes SJ, Economou G, Whitehouse RW, Adams JE, Shalet SM. Reduced bone mineral density in patients with adult onset growth hormone deficiency. J Clin Endocrinol Metab 1994; 78: 669-74.         [ Links ]
37. Kaufman JM, Taelman P, Vermeulen A, Vandeweghe M. Bone mineral status in growth hormone-deficient males with isolated and multiple pituitary deficiencies of childhood onset. J Clin Endocrinol Metab 1992; 74: 118-23.         [ Links ]
38. Rosen T, Wilhelmsen L, Landin-Wilhelmsen K, Lappas G, Bengtsson BA. Increased fracture frequency in adult patients with hypopituitarism and GH deficiency. Eur J Endocrinol 1997; 137: 240-5.         [ Links ]
39. Balducci R, Toscano U, Pasquino AM et al. Bone Turnover and Bone Mineral Density in Young Adult Patients with Panhypopituitarism before and after Long-term Growth Hormone Therapy. Eur J Endocrinol 1995; 132: 42-6.         [ Links ]
40. Simpson H, Savina R, Sörksen R et al. Growth Hormone Replacement Therapy for adults: Into the New Millennium. Growth Horm IGF Res 2002; 12: 1-33.         [ Links ]
41. Ferretti JL, Schiessl H, Frost HM. On new opportunities for absorptiometry. J Clin Densitometry 1998; 1: 41-53.         [ Links ]

Received: 14-07-2003
Accepted: 21-10-2003